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cADPR Does Not Activate TRPM2
cADPR is a second messenger that releases Ca(2+) from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activat...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949931/ https://www.ncbi.nlm.nih.gov/pubmed/35328585 http://dx.doi.org/10.3390/ijms23063163 |
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author | Riekehr, Winnie Maria Sander, Simon Pick, Jelena Tidow, Henning Bauche, Andreas Guse, Andreas H. Fliegert, Ralf |
author_facet | Riekehr, Winnie Maria Sander, Simon Pick, Jelena Tidow, Henning Bauche, Andreas Guse, Andreas H. Fliegert, Ralf |
author_sort | Riekehr, Winnie Maria |
collection | PubMed |
description | cADPR is a second messenger that releases Ca(2+) from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activation of TRPM2 by cADPR alone or in synergy with ADPR, sometimes only at 37 °C, others have argued that this is due to the contamination of cADPR by ADPR. The identification of a novel nucleotide-binding site in the N-terminus of TRPM2 that binds ADPR in a horseshoe-like conformation resembling cADPR as well as the cADPR antagonist 8-Br-cADPR, and another report that demonstrates activation of TRPM2 by binding of cADPR to the NUDT9H domain raised the question again and led us to revisit the topic. Here we show that (i) the N-terminal MHR1/2 domain and the C-terminal NUDT9H domain are required for activation of human TRPM2 by ADPR and 2′-deoxy-ADPR (2dADPR), (ii) that pure cADPR does not activate TRPM2 under a variety of conditions that have previously been shown to result in channel activation, (iii) the cADPR antagonist 8-Br-cADPR also inhibits activation of TRPM2 by ADPR, and (iv) cADPR does not bind to the MHR1/2 domain of TRPM2 while ADPR does. |
format | Online Article Text |
id | pubmed-8949931 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89499312022-03-26 cADPR Does Not Activate TRPM2 Riekehr, Winnie Maria Sander, Simon Pick, Jelena Tidow, Henning Bauche, Andreas Guse, Andreas H. Fliegert, Ralf Int J Mol Sci Article cADPR is a second messenger that releases Ca(2+) from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activation of TRPM2 by cADPR alone or in synergy with ADPR, sometimes only at 37 °C, others have argued that this is due to the contamination of cADPR by ADPR. The identification of a novel nucleotide-binding site in the N-terminus of TRPM2 that binds ADPR in a horseshoe-like conformation resembling cADPR as well as the cADPR antagonist 8-Br-cADPR, and another report that demonstrates activation of TRPM2 by binding of cADPR to the NUDT9H domain raised the question again and led us to revisit the topic. Here we show that (i) the N-terminal MHR1/2 domain and the C-terminal NUDT9H domain are required for activation of human TRPM2 by ADPR and 2′-deoxy-ADPR (2dADPR), (ii) that pure cADPR does not activate TRPM2 under a variety of conditions that have previously been shown to result in channel activation, (iii) the cADPR antagonist 8-Br-cADPR also inhibits activation of TRPM2 by ADPR, and (iv) cADPR does not bind to the MHR1/2 domain of TRPM2 while ADPR does. MDPI 2022-03-15 /pmc/articles/PMC8949931/ /pubmed/35328585 http://dx.doi.org/10.3390/ijms23063163 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Riekehr, Winnie Maria Sander, Simon Pick, Jelena Tidow, Henning Bauche, Andreas Guse, Andreas H. Fliegert, Ralf cADPR Does Not Activate TRPM2 |
title | cADPR Does Not Activate TRPM2 |
title_full | cADPR Does Not Activate TRPM2 |
title_fullStr | cADPR Does Not Activate TRPM2 |
title_full_unstemmed | cADPR Does Not Activate TRPM2 |
title_short | cADPR Does Not Activate TRPM2 |
title_sort | cadpr does not activate trpm2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949931/ https://www.ncbi.nlm.nih.gov/pubmed/35328585 http://dx.doi.org/10.3390/ijms23063163 |
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